Preclinical activity of selinexor in combination with eribulin in uterine leiomyosarcoma

Experimental Hematology & Oncology

Correspondence

Sonam Mittal¹  Shirng-Wern Tsaih¹  Sudhir Kumar¹  Ishaque Pulikkal Kadamberi¹  Pradeep Chaluvally-Raghavan²  Sunila Pradeep²  Feng Wang³  Hua Chang³  Christopher J. Walker³  Yosef Landesman³  John Charlson⁴ 

[1] Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA;Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, WI, USA;Medical College of Wisconsin-Cancer Center, Milwaukee, WI, USA;Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA;Karyopharm Therapeutics, Inc, Newton, MA, USA;Medical Oncology, Medical College of Wisconsin, 53226, Milwaukee, WI, USA;

关键词: LMS;    ULMS;    XPO1;    Sarcoma;    Eribulin;    Selinexor;    Doxorubicin;   

DOI  :  10.1186/s40164-023-00443-w

 received in 2023-06-23, accepted in 2023-09-08,  发布年份 2023

来源: Springer

【 摘 要 】

Leiomyosarcoma (LMS) is a rare soft tissue sarcoma (STS) that begins in smooth muscle tissue and most often initiates in the abdomen or uterus. Compared with other uterine cancers, uterine LMS (ULMS) is an aggressive tumor with poor prognosis and a high risk of recurrence and death, regardless of the stage at presentation. Selinexor is a first-in-class selective inhibitor of nuclear export (SINE) compound that reversibly binds to exportin 1 (XPO1), thereby reactivating tumor suppressor proteins and downregulating the expression of oncogenes and DNA damage repair (DDR) proteins. In this study, we evaluated the effects of selinexor in combination with doxorubicin and eribulin in the LMS tumor model in vitro and in vivo. Treatment of selinexor combined with eribulin showed synergistic effects on tumor growth inhibition in SK-UT1 LMS-derived xenografts. Immunohistochemical assessment of the tumor tissues showed a significantly reduced expression of proliferation (Ki67) and XPO1 markers following combination therapy compared to the control group. Global transcriptome analyses on tumor tissue revealed that the combination therapy regulates genes from several key cancer-related pathways that are differentially expressed in ULMS tumors. To our knowledge, this is the first preclinical study demonstrating the anti-cancer therapeutic potential of using a combination of selinexor and eribulin in vivo. Results from this study further warrant clinical testing a combination of chemotherapy agents with selinexor to reduce the morbidity and mortality from ULMS.

【 授权许可】

CC BY   
© YUMED Inc. and BioMed Central Ltd. 2023

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